TY - JOUR

T1 - The functional insight into the geneticsof cardiovascular disease: results from the post-GWAS study

AU - Bryzgalov, L. O.

AU - Korbolina, E. E.

AU - Damarov, I. S.

AU - Merkulova, T.

N1 - The functional insight into the geneticsof cardiovascular disease: results from the post-GWAS study / L. O. Bryzgalov, E. E. Korbolina, I. S. Damarov, T. I. Merkulova // Vavilov Journal of Genetics and Breeding. – 2022. – Vol. 26. – No 1. – P. 65-73. Funding Information: We greatly thank the people who contributed to a valuable, worldwide reference for human genetic variation, 1000 Genomes Project, by contributing their samples and their efforts. The study was funded by the grant 18-29-09041 from the Russian Foundation for Basic Research and the State Budget Project FWNR-2022-0016. Publisher Copyright: © Bryzgalov L.O., Korbolina E.E., Damarov I.S., Merkulova T.I., 2022 This work is licensed under a Creative Commons Attribution 4.0 License

PY - 2022/2

Y1 - 2022/2

N2 - Cardiovascular diseases (CVDs), the leading cause of death worldwide, generally refer to a range of pathological conditions with the involvement of the heart and the blood vessels. A sizable fraction of the susceptibility loci is known, but the underlying mechanisms have been established only for a small proportion. Therefore, there is an increasing need to explore the functional relevance of trait-associated variants and, moreover, to search for novel risk genetic variation. We have reported the bioinformatic approach allowing effective identification of functional non-coding variants by integrated analysis of genome-wide data. Here, the analysis of 1361 previously identified regulatory SNPs (rSNPs) was performed to provide new insights into cardiovascular risk. We found 773,471 coding co-segregating markers for input rSNPs using the 1000 Genomes Project. The intersection of GWAS-derived SNPs with a relevance to cardiovascular traits with these markers was analyzed within a window of 10 Kbp. The effects on the transcription factor (TF) binding sites were explored by DeFine models. Functional pathway enrichment and protein-protein interaction (PPI) network analyses were performed on the targets and the extended genes by STRING and DAVID. Eighteen rSNPs were functionally linked to cardiovascular risk. A significant impact on binding sites of thirteen TFs including those involved in blood cells formation, hematopoiesis, macrophage function, inflammation, and vasoconstriction was found in K562 cells. 21 rSNP gene targets and 5 partners predicted by PPI were enriched for spliceosome and endocytosis KEGG pathways, endosome sorting complex and mRNA splicing REACTOME pathways. Related Gene Ontology terms included mRNA splicing and processing, endosome transport and protein catabolic processes. Together, the findings provide further insight into the biological basis of CVDs and highlight the importance of the precise regulation of splicing and alternative splicing.

AB - Cardiovascular diseases (CVDs), the leading cause of death worldwide, generally refer to a range of pathological conditions with the involvement of the heart and the blood vessels. A sizable fraction of the susceptibility loci is known, but the underlying mechanisms have been established only for a small proportion. Therefore, there is an increasing need to explore the functional relevance of trait-associated variants and, moreover, to search for novel risk genetic variation. We have reported the bioinformatic approach allowing effective identification of functional non-coding variants by integrated analysis of genome-wide data. Here, the analysis of 1361 previously identified regulatory SNPs (rSNPs) was performed to provide new insights into cardiovascular risk. We found 773,471 coding co-segregating markers for input rSNPs using the 1000 Genomes Project. The intersection of GWAS-derived SNPs with a relevance to cardiovascular traits with these markers was analyzed within a window of 10 Kbp. The effects on the transcription factor (TF) binding sites were explored by DeFine models. Functional pathway enrichment and protein-protein interaction (PPI) network analyses were performed on the targets and the extended genes by STRING and DAVID. Eighteen rSNPs were functionally linked to cardiovascular risk. A significant impact on binding sites of thirteen TFs including those involved in blood cells formation, hematopoiesis, macrophage function, inflammation, and vasoconstriction was found in K562 cells. 21 rSNP gene targets and 5 partners predicted by PPI were enriched for spliceosome and endocytosis KEGG pathways, endosome sorting complex and mRNA splicing REACTOME pathways. Related Gene Ontology terms included mRNA splicing and processing, endosome transport and protein catabolic processes. Together, the findings provide further insight into the biological basis of CVDs and highlight the importance of the precise regulation of splicing and alternative splicing.

KW - non-coding genetic variation

KW - rSNPs

KW - cardio-vascular disease risk

KW - GWAS association

KW - 1000 Genomes Project

KW - gene expression regulation

KW - transcription factor binding

KW - GENOME-WIDE ASSOCIATION

KW - HEART

KW - DYSFUNCTION

KW - BINDING

KW - MACHINERY

KW - PATHWAYS

KW - TRAITS

KW - PIEZO1

KW - COUNT

KW - LIVER

KW - 1000 Genomes Project

KW - cardio-vascular disease risk

KW - gene expression regulation

KW - GWAS association

KW - non-coding genetic variation

KW - rSNPs

KW - transcription factor binding

UR - http://www.scopus.com/inward/record.url?scp=85133098066&partnerID=8YFLogxK

UR - https://elibrary.ru/item.asp?id=48021027

UR - https://www.mendeley.com/catalogue/4ba7f07f-ecbf-31ca-85a4-d3afad316c4f/

U2 - 10.18699/VJGB-22-10

DO - 10.18699/VJGB-22-10

M3 - Article

C2 - 35342858

VL - 26

SP - 65

EP - 73

JO - Вавиловский журнал генетики и селекции

JF - Вавиловский журнал генетики и селекции

SN - 2500-0462

IS - 1

M1 - 8

ER -